Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

Early hospital readmissions post-kidney transplantation are associated with inferior clinical outcomes.

Unplanned hospital readmissions are common early post-kidney transplantation. We investigated the relationship between early hospital readmissions and clinical outcomes in a single-center retrospective study that included all adult kidney transplant patients between 2004 and 2008 with follow-up to December 2012. The early hospital readmissions within the first 30 d were numbered and the diagnosis ascertained. Patients were grouped as none, once, and twice or more readmissions. Predictors of early readmissions were assessed, and clinical outcomes and patient and death-censored kidney survival were compared. Among 1064 patients, 203 (19.1%) patients had once and 83 (7.8%) patients had twice or more readmissions within 30 d. Surgical complications, infections, and acute kidney injuries/acute rejection were three most common diagnoses. The length of initial hospital stay and African American race were among the variables associated significantly with readmissions. Patients with early readmissions had lower baseline renal function (p < 0.01) and more early acute rejection (p < 0.01). During follow-up, only frequent readmissions, twice or more, within 30 d were associated with increased risk of death (AHR 1.75, p = 0.01) and death-censored kidney failure (AHR 2.20, p < 0.01). Frequent early hospital readmissions post-transplantation identify patients at risk for poor long-term outcomes, and more studies are needed to understand the mechanisms.

Six-month low-dose valganciclovir prophylaxis in cytomegalovirus D+/R- kidney transplant patients receiving thymoglobulin induction.

BACKGROUND: The use of T-cell-depleting antibody, such as thymoglobulin, is a risk factor for cytomegalovirus (CMV) infection. We studied the effectiveness of 6 months of low-dose valganciclovir prophylaxis in CMV-naive kidney transplant recipients of CMV-positive donor kidney (D+/R-) receiving thymoglobulin induction. METHODS: We included all D+/R- kidney transplant patients between October 2005 and December 2010 who received valganciclovir 450 mg daily for 6 months as per center protocol. CMV infection was confirmed by positive viremia. Kaplan-Meier and multivariate Cox proportional regression analyses were employed to compare the risk of CMV infection between patients with and without the use of thymoglobulin induction. RESULTS: Out of 170 D+/R- kidney transplant patients, 42 cases of CMV infection (24.6%) were diagnosed after a median follow-up of 3.2 years: six patients from the noninduction (9.4%) and 36 from the induction cohort (34.0%). The induction with thymoglobulin was associated with four times greater risk of developing CMV infection (adjusted hazard ratio: AHR 4.15, 95% 1.75, 9.86, P = .001). The use of thymoglobulin was associated with leukopenia but not neutropenia. CONCLUSIONS: Additional measures are needed to reduce the elevated incidence of CMV infection in D+/R- kidney transplant patients receiving induction with thymoglobulin.

Impact of cytomegalovirus disease in D+/R- kidney transplant patients receiving 6 months low-dose valganciclovir prophylaxis.

Late-onset cytomegalovirus (CMV) disease remains common in CMV serology naïve kidney transplant patients of CMV serology positive organs (D+/R-) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6-month low-dose valganciclovir (VGCV) prophylaxis, risk factors for late-onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R- kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow-up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively. The use of an induction agent with rabbit antithymocyte globulin and older donor age were factors associated with the risk of late-onset CMV disease (AHR 2.91, 95% CI 1.18-7.20, p = 0.021 and AHR 1.03, 95% CI 1.01-1.06, p = 0.016, respectively). Late-onset CMV disease was associated with increased risk for death-uncensored graft loss (AHR 2.95, 95% CI 1.15-7.61, p = 0.025). In conclusion, late-onset CMV disease continues to negatively impact kidney transplant outcome despite 6-month low-dose VGCV prophylaxis. Investigations focusing on novel preventive approaches should be emphasized.

Influence of recipient race on the outcome of simultaneous pancreas and kidney transplantation.

Racial differences on the outcome of simultaneous pancreas and kidney (SPK) transplantation have not been well studied. We compared mortality and graft survival of African Americans (AA) recipients to other racial/ethnic groups (non-AA) using the national data. We studied a total of 6585 adult SPK transplants performed in the United States between January 1, 2000 and December 31, 2007. We performed multivariate logistic regression analyses to determine risk factors associated with early graft failure and immune-mediated late graft loss. We used conditional Kaplan-Meier survival and multivariate Cox regression analyses to estimate late death-censored kidney and pancreas graft failure and death between the groups. Although there was no racial disparity in the first 90 days, AA patients had 38% and 47% higher risk for late death-censored kidney and pancreas graft failure, respectively (p = 0.006 and 0.001). AA patients were twice more likely to lose the kidney and pancreas graft due to rejection (OR 2.31 and 1.86, p = 0.002 and 0.008, respectively). Bladder pancreas drainage was associated with inferior patient survival (HR 1.42, 95% CI 1.15, 1.75, p = 0.001). In the era of modern immunosuppression, AA SPK transplant patients continue to have inferior graft outcome. Additional studies to explore the mechanisms of such racial disparity are warranted.

Choice of induction regimens on the risk of cytomegalovirus infection in donor-positive and recipient-negative kidney transplant recipients.

BACKGROUND: Late occurrence of cytomegalovirus (CMV) infection remains a concern in CMV-seronegative kidney and/or pancreas transplant recipients of CMV-seropositive organs (donor positive/recipient negative, D+/R-) despite the use of prophylaxis. We investigated the impact of various antibody induction regimens on CMV infection in this group of patients. METHODS: A total of 254 consecutive D+/R- kidney and/or pancreas transplant patients were studied. The induction agents rabbit anti-thymocyte globulin (rATG) or basiliximab were used according to the center practice. All patients received prophylaxis with valganciclovir (VGCV) for either 3 or 6 months. The occurrence of CMV infection was confirmed by positive DNA viremia. Multivariate Cox regression analyses were performed to determine risk factors for CMV infection. RESULTS: The cumulative incidence of CMV infection was 58, 112, and 59 cases per 1000 patient-years for patients who received no antibody induction, induction with rATG, or basiliximab induction, respectively (P=0.02). The use of rATG but not basiliximab was associated with an increased risk for CMV infection (adjusted hazard ratio [AHR] 2.13, 95% confidence interval [CI] 1.24-3.54, P=0.006). Acute rejection and its treatment with rATG were not associated with an increased risk for CMV infection when an additional course of VGCV was given following the treatment. Longer duration of prophylaxis was associated with a reduced risk for CMV infection (AHR 0.54, 95% CI 0.33-0.87, P=0.011). CONCLUSIONS: Induction with rATG is associated with increased risk of CMV infection. Longer duration of prophylaxis is beneficial.

Graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression.

Steroid-free regimen is increasingly employed in kidney transplant recipients across transplant centers. However, concern remains because of the unknown impact of such an approach on long-term graft and patient survival. We studied the outcomes of steroid-free immunosuppression in a population-based U.S. cohort of kidney transplant recipients. All adult solitary kidney transplant recipients engrafted between January 1, 2000 and December 31, 2006 were stratified according to whether they were selected for a steroid-free or steroid-containing regimen at discharge. Multivariate Cox regression models were used to estimate graft and patient survival. The impact of the practice pattern on steroid use at individual transplant centers was analyzed. Among 95 755 kidney transplant recipients, 17.2% were steroid-free at discharge (n = 16 491). Selection for a steroid-free regimen was associated with reduced risks for graft failure and death at 1 year (HR 0.78, 95% CI 0.72-0.85, and HR 0.73, 95% CI 0.65-0.82, respectively, p < 0.0001) and 4 years (HR 0.83, 95% CI 0.78-0.87, and HR 0.76, 95% CI 0.71-0.83, respectively, p < 0.0001). This association was mostly observed at individual centers where less than 65% of recipients were discharged on the steroid-containing regimen. De novo steroid-free immunosuppression as currently practiced in the United States appears to carry no increased risk of adverse clinical outcomes in the intermediate term.

Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period.

New onset diabetes after transplantation (NODAT) and impaired fasting glucose (IFG) are common in kidney transplant recipients (KTRs). Calcinuerin inhibitor (CNI) therapy is a causal risk factor. NODAT is associated with increased mortality and diminished graft survival. We studied the incidence of NODAT and IFG in KTRs before and after a medically indicated switch of CNI therapy from cyclosporine (CsA) to tacrolimus (Tac). The study population consisted of 704 nondiabetic KTRs. Of them, 171 underwent conversion from CsA to Tac (group I) and 533 remained on the CsA since transplantation (Group II). Time-dependent Cox regression and generalized estimating equations were used to account for sequential CNI exposure. NODAT and IFG occurred in 15.2% and 22.1% of group I subjects and 15.6% and 25.8% of group II subjects, respectively (p = 0.90 for NODAT and p = 0.38 for IFG). Accounting for equal follow-up time since conversion from CsA to Tac, the adjusted 5-year NODAT-free survival was 87.4% and 91.4% in group I and group II, respectively (p = 0.90). In conclusion, conversion to Tac, compared to continuous exposure to CsA, carries quantitatively similar risk of impaired glucose metabolism in KTRs in the late posttransplant period.

Efficacy of valganciclovir in the treatment of cytomegalovirus disease in kidney and pancreas transplant recipients.

Cytomegalovirus (CMV) disease is relatively common following solid organ transplant, particularly if a serologically negative recipient receives an organ from a serologically positive donor (D+/R-). Although valganciclovir is approved for the treatment of CMV retinitis in AIDS patients and is used for the prophylaxis against CMV infection in solid organ transplant patients, the current standard treatment for CMV disease in solid organ transplant recipients remains intravenous ganciclovir. We retrospectively reviewed our experience using valganciclovir as treatment for CMV disease in CMV D+/R- kidney and/or pancreas transplant recipients from March 2002 to June 2005. A total of 37 cases with primary CMV disease were diagnosed and treated with either intravenous ganciclovir as induction followed with valganciclovir or valganciclovir from the beginning. We compared clinical outcomes and viremia between the two groups. Our data suggest that valganciclovir is an effective treatment modality for primary CMV disease in kidney and/or pancreas transplant recipients. It led to the resolution of disease and undetectable viremia. Valganciclovir allowed for early initiation of treatment and for treatment to be given as an outpatient. These advantages of valganciclovir have both health and economic impact for patients with CMV disease.

Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice.

OBJECTIVE: To analyze the structure, specificity, and in vivo pathogenetic potential of 2 human anticardiolipin (aCL) monoclonal antibodies (MAb). METHODS: Human aCL IgG MAb were generated from hybridized Epstein-Barr virus-induced B cell lines from a healthy subject (MAb 519) and from a patient with primary antiphospholipid syndrome (MAb 516). Studies of antigen-binding specificity and analysis of Ig V-gene mutations were carried out. The MAb were independently injected into mated female BALB/c mice, and their effect on pregnancy outcome was compared with that of MAb 57, a highly mutated and antigen-selected human IgG1lambda rabies virus antibody. RESULTS: Both MAb 519 and MAb 516 utilized minimally mutated V(H)DJ(H) and VkappaJkappa gene segments and bound cardiolipin and other anionic phospholipids in the absence of beta2-glycoprotein I (beta2-GPI). The mice injected with aCL MAb displayed a significantly higher rate of fetal resorption and a significant reduction in fetal and placental weight as compared with those injected with MAb 57. These findings were accompanied by a finding of placental human IgG deposition and necrosis in the aCL MAb-treated animals. CONCLUSION: The results of this study indicate that human aCL IgG that are beta2-GPI independent can induce pathology.

Chronic fatigue: a peculiar evolution of eosinophilia myalgia syndrome following treatment with L-tryptophan in four Italian adolescents.

We describe four Italian adolescents in whom a persistent, debilitating fatigue appeared after therapeutic ingestion of products containing L-tryptophan and subsequent to the development of a transient rise in eosinophil count and severe myalgia (Eosinophilia Myalgia Syndrome-EMS). Their clinical picture was indistinguishable from that of the so-called Chronic Fatigue Syndrome. A chronic fatigue may occur after diverse triggering agents and its represents the peculiar clinical evolution of these four paediatric cases of EMS.

Anti-cardiolipin antibodies in HIV infection are true antiphospholipids not associated with antiphospholipid syndrome.

The aim of the present study was to evaluate the fine specificity of anticardiolipin (aCL) antibodies detectable in the sera of patients with HIV infection. aCL are generally associated with thrombotic events in autoimmune diseases. A solid phase ELISA which discriminates between aCL binding to phospholipids and aCL binding to phospholipid/beta 2-glycoprotein I (cofactor) complex was employed. Thirty-nine HIV and 20 aCL positive systemic lupus erythematosus (SLE) sera were examined. In HIV sera, reduced binding to phospholipid was seen if cofactor was added. On the contrary, in SLE-sera the cofactor improved aCL binding. No thrombotic events were recorded in HIV infected subjects presenting with aCL. Thus, aCL in HIV infection and in SLE appear to have different specificities. In HIV infection the true epitope of aCL is likely to be on the phospholipid component only, whereas in SLE aCL seem directed against the cofactor/CL complex. Considering the anticoagulant role of beta 2-glycoprotein I, this observation might account for the lack of thrombosis in HIV patients with "true" aCL.

Geographical clustering of scleroderma in a rural area in the province of Rome.

A geographical cluster of scleroderma and scleroderma-related features was identified in a rural area in the province of Rome. Two patients with scleroderma, three with CREST syndrome and one with eosinophilic fasciitis were living in a village where the total population included 572 persons of voting age. No kindred relationships were demonstrable among these patients. Clinical features of scleroderma such as Raynaud's phenomenon, bilateral hand edema, and digital scars were detected in an additional 10 cases. A group of apparently healthy subjects with scleroderma-related serological abnormalities (circulating antinuclear and anticentriole autoantibodies) was also identified in the village. No disease-associated HLA antigen in the patients nor genetic differences between patients and healthy subjects living in the same village were detected by HLA typing. Some still unidentified environmental factors acting on genetically predisposed subjects may be responsible for the clustering of the disease seen in this study.